Method for manufacturing radioactive brachytherapy source material, brachytherapy source material and encapsulated radioactive brachytherapy source

ABSTRACT

The invention relates to a method for producing a radioactive brachytherapy source material comprising indium-114m in radioactive equilibrium with indium-114 as main radioactive isotopes. A new radioactive brachytherapy source material comprises indium-114m in radioactive equilibrium with indium-114 as main radioactive isotopes. A new encapsulated radioactive brachytherapy source comprises the new radioactive brachytherapy source material.

[0001] This application is a divisional of co-pending application Ser.No. 09/660,637, filed on Sep. 13, 2000, the entire contents of which arehereby incorporated by reference and for which priority is claimed under35 U.S.C. § 120; and this application claims priority of applicationSer. No. 1013036 filed in The Netherlands on Sep. 14, 1999 under 35U.S.C. § 119.

[0002] The invention relates to a method for manufacturing radioactivebrachytherapy source material.

[0003] The invention also relates to a radioactive brachytherapy sourcematerial.

[0004] The invention also relates to encapsulated radioactivebrachytherapy sources comprising a radioactive brachytherapy sourcematerial.

BACKGROUND OF THE INVENTION

[0005] Brachytherapy as used herein is defined as therapy performed onmammals in which radioactive sources are brought in the near vicinity oftissue to be treated. Conventionally the tissue to be treated was mainlycancerous tissue. Since the early nineteen nineties a new field hasstarted using brachytherapy, namely endovascular brachytherapy of bloodvessels that have been subjected to angioplasty. It has been discoveredthat irradiation of the angioplasty site before, during or after theperformance of the angioplasty may significantly reduce restenosis ofthe site. Restenosis is the re-occlusion of a vessel due to tissuegrowth and vessel remodeling after the angioplasty procedure.Endovascular brachytherapy has been described in Bertrand, O. F. et al;Intravascular radiation therapy in atherosclerotic disease: promises andpremises; European Heart Journal, (1997) 18, pag. 1385-1395; Diamond, D.A. et al; The Role of Radiation Therapy in the Management of VascularRestenosis. Part II. Radiation Techniques and Results; JVIR (1998)9,pag. 389-400; Baumgart, D. et al; Die intravasale Strahlenbehandlung zurkombinierten Therapie und Prävention der Restenosierung; Herz1977;22:335-346(Nr.6); Baiter, S.; Endovascular Brachytherapy: Physicsand Technology; Catheterization and Cardiovascular Diagnosis45:292-298(1998) and Nath, R. et al; Intravascular brachytherapyphysics: Report of the AAPM Radiation Therapy Committee Task group No.60; Med. Phys. 26(2), February 1999, pag. 119-152, Ron Waksman (ed):Vascular Brachytherapy, Second Edition, Future Publishing Company, Inc,1999, Armonk, N.Y. and Waksman, R. et al: Vascular Brachytherapy,Nucletron B. V., 1996, Veenendaal, the Netherlands.

[0006] In various applications of brachytherapy a radioactivebrachytherapy source is brought into the vicinity of the tissue to betreated through a tube like device such as a catheter. Such a tube likedevice is also known as a guide tube.

[0007] Radioactive brachytherapy sources have been described in a numberof patents and other references. An exemplary embodiment of suchdescription is known from U.S. Pat. No. 4,861,520. The source describedtherein comprises a steel capsule. An opening of the capsule is weldedto a plug. The plug is welded in turn to a steel cable. Inside thecapsule a number of radioactive iridium-192 pellets is present.

[0008] Another exemplary embodiment of a radioactive brachytherapysource may be found in U.S. Pat. No. 5,084,001. Therein is shown anddescribed a relatively pure platinum wire with near one of its tips arod like piece of iridium-192 fully encapsulated by the platinum.

[0009] A further exemplary embodiment of a radioactive brachytherapysource is shown and described in international patent application WO94/25106. Therein is shown and described a nickel-titanium wire with alongitudinal, axially directed cavity at a tip. That cavity is filledwith a number of iridium-192 spheres.

[0010] A still further embodiment of a radioactive brachytherapy sourceis shown and described in international patent application WO 92/00776.Therein is shown and described a source comparable to the source shownin U.S. Pat. No. 4,861,520, however, with a single elongated rod ofradioactive material in place of a number of pellets.

[0011] Further embodiments of radioactive brachytherapy sources areshown and described in the United States Registry of RadioactiveEncapsulated Sources and Devices. The Registry may be approached throughthe Internet at website

[0012] http://www.hsrd.ornl.gov/nrc/ssdr/ssdrindj.htm#J.K

[0013] Registration No. LA-0557-S-102-S describes and shows an iridiumwire encapsulated with a 3 micron titanium coating. The titanium coatingforms a hard (flexible) shell around the Ir-192 wire. The Ir-192 wire ispositioned and encapsulated inside a nickel/titanium tube that has acavity formed by a nickel titanium wire that runs the entire length ofthe tube and stops short of the last 32 mm. This forms the cavity thataccepts the 30 mm long Ir-192 wire. The backbone wire is welded to thedistal end of the tube to form a tight seal. The Ir-192 wire is placedinto the cavity created inside the tube and the proximal end of the tubeis welded shut to firmly encapsulate the Ir-192 wire.

[0014] Registration No. LA-0760-S-102-S describes and shows a 10 mm longIr-192 seed encapsulated firmly inside a solid titanium/nickel wire. TheIr-192 seed is inserted into a hole drilled into an end of thetitanium/nickel wire.

[0015] Registration No. LA-0760-S-105-S describes and shows a P-32source. A thin film of P-32 is deposited within a carrier tube. Thecarrier tube is inserted into a cylindrical cavity at an end of anickel/titanium tube, which has been welded on a nickel/titanium wire. Atungsten wire marker is inserted into the tube at the distal end of thecarrier tube. A nickel titanium plug is inserted in the distal tip ofthe tube cavity and then welded to form a seal.

[0016] Handbook of Vascular Brachytherapy, ed. Ron Waksman and PatrickW. Serruys, Martin Dunitz Ltd, 1998, London at pages 489-497 show abrachytherapy source delivery system in which a “train” of severalminiature cylindrical encapsulated sources containing Sr-90/Y-90 isdelivered to the angioplasty site through a catheter by means of afluid.

[0017] Registration No. NR-569-S-101-S describes and shows encapsulatedradioactive gold seeds. Each cylindrical seed contains a rod of gold,which is encased in a platinum sheath.

[0018] Registration No. GA-1061-S-101-S describes and shows a tube likesource. The source is constructed by centering a platinum-iridium markeron the outer surface of a medical grade titanium inner tube, followed bya layer of Pd-103 suspended homogeneously in a water insoluble organicpolymer matrix. The source is encapsulated by sliding an outer tube overthe inner tube and laser welding both ends.

[0019] Registration No. NR-187-S-103-S describes and shows a substratewith adsorbed onto it either iodine-125 or cesium-131 or palladium-103in liquid form. Substrates for iodine may be rods or balls of carbon,polytyrosine or an anion exchange resin. Also described is a solid pieceof samarium-145. The source material is encapsulated in a cylindricaldouble-walled titanium capsule and encapsulated by laser weld.

[0020] Registration No. IL-136-S-338-S describes and shows iodine-125absorbed on a solid silver bar and encapsulated in a cylindricaltitanium capsule.

[0021] Registration No. IL-136-S-337-S describes and shows iodine-125absorbed on anion exchange resin spheres and encapsulated in acylindrical titanium capsule.

[0022] Registration No. CA0510S126S describes and shows palladium-103electroplated on a metallic substrate or absorbed on ion exchange resinbeads. The active element is then placed inside a titanium capsule,which is then welded on its ends to complete containment.

[0023] Depending on the type of tissue that has to be irradiated achoice for a radioactive isotope is to be made that is to be used in theradioactive brachytherapy source.

[0024] The above described and practically used sources make use of amultitude of isotopes.

[0025] Still more potential isotopes are described in U.S. Pat. No.5,342,283. A considerable number of tables show for various desiredbeta- or gamma radiation outputs which isotopes of which elementsproduce such desired radiation. The patent is directed to coating piecesof a first material with one or more layers of second etc. materials.

[0026] U.S. Pat. No. 5,302,369 shows a method of manufacturing glassspheres containing a radioactive isotope. The glass spheres havediameters between 5 and 75 micron. First the glass spheres aremanufactured such that they contain a precursor of the desiredradioactive isotope. Thereafter the glass spheres are irradiated byneutron radiation to convert the precursor into the desired radioactiveisotope. Other elements present in the glass spheres are selected fromthe group consisting of elements that do not become radioactive duringneutron irradiation and elements that have a half life that issufficiently short so that the other elements altogether do not emit asignificant amount of beta- or gamma radiation at the time ofadministration of the radiation.

[0027] Radioactive brachytherapy source materials for incorporation in aradioactive brachytherapy source come in various shapes. Well known fromthe abovedescribed sources are spheres, microspheres, rods, pellets,cylindrically shaped, short rods, beads. Further known are ellipsoidlike and lens like shapes.

[0028] In endovascular brachytherapy, especially for coronaryapplications, an encapsulated radioactive brachytherapy source isdesired that can navigate short curves without getting stuck or piercinga catheter or vessel wall. Such a source preferably is not larger indiameter than about 1 mm. Consequently, the specific activity, i.e. theactivity per unit mass, of the radioactive brachyhtherapy sourcematerial should be sufficiently high to allow the construction of a thinsource with a sufficiently high source strength to limit treatment timesto preferably no more than several minitues. Furthermore at least forcertain endovascular brachytherapy applications a beta source may bedesirable, i.e. a source that predominantly radiates beta radiation.Beta radiation has a relatively short range in tissue, i.e. the betaparticles do not penetrate deeper into tissue than several millimeters.Thus an encapsulated radioactive brachytherapy source of beta radiationallows localized irradiation of the vessel wall without exposing oytherbody parts of the patient to radiation. Furthermore radiation exposureof medical personnel residing close to the patient is minimized,allowing the irradiation procedure to be performed adjacent to theangioplasty procedure within the ordinary cathlab environment withoutneed for extensive shielding. A problem encountered in beta radiationsource materials used in practice is that the mean energy of the betaradiation of many radionuclides is on the low side for brachytherapyapplications. Another problem encountered in beta radiation sources is ashort half life. In fact, it is known from nuclear physics thatgenerally the half life of beta emitting radionuclides is relativelyshort when the beta energy is high. Too short a half life results inlogistics problems as a consequence of the fact that an installed sourcehas to be replaced with a new source after a short period already. It isdesired to produce the radioactive source material both economically andreliably. Reliability of supply is important to assure that decayedsources can be replaced in time and requires that the source materialcan be produced by means of readily available production facilities,including e.g. nuclear radio isotope production reactors.

[0029] Consequently, a need has remained for a radioactive brachytherapysource material that emits beta radiation of sufficiently high energyand has a sufficiently long half life, that can be produced at asufficiently high specific activity to allow short treatment times thatcan be produced both economically and reliably and that will allow theconstruction of a thin, encapsulated radioactive brachytherapy source inwhich that material has been applied to navigate short curves incoronary vessels and that may also have applications in otherbrachytherapy fields.

SUMMARY OF THE INVENTION

[0030] An object of the invention is to provide a method ofmanufacturing radioactive brachytherapy source material comprisingindium-114m in radioactive equilibrium with indium-114 as mainradioactive isotopes, said method comprising manufacturing predefinedlyshaped pieces of a substantially inorganic and inactive materialcomprising indium oxide, the indium in said indium oxide having anabundance of indium-113 substantially equal to or greater than itsnatural abundance and subsequently subjecting the predefinedly shapedpieces of material to neutron irradiation until a predetermined specificactivity of indium-114m of at least one MegaBequerel per gram indium hasbeen reached.

[0031] With the expression main radioactive isotopes as used throughoutthe present description and claims is meant that a therapeutic dosedistribution about a radioactive brachytherapy source, i.e. atherapeutically relevant dose distribution, is mainly determined by saidmain radioactive isotopes. The expression mainly determined as usedthroughout the present description and claims means that thecontribution and claims means that the contribution to the therapeuticdose distribution of radiation emitted by radionuchides other than tenpercent of the contribution to the therapeutic dose distribution ofradiation emitted by indium-114m and indium-114.

[0032] A further object of the invention is to provide such a method inwhich the predefinedly shaped pieces comprise substantially only indiumoxide.

[0033] A still further object of the invention is to provide aradioactive brachytherapy source material comprising predefinedly shapedpieces of material of a substantially inorganic material comprisingindium oxide, the indium, present in said indium oxide, comprisingindium-114m in radioactive equilibrium with indium-114 as mainradioactive isotopes, said indium-114m being present with a specificactivity of at least one MegaBequerel per gram indium.

[0034] A still further. object of the invention is to provide aradioactive brachytherapy source material comprising predefinedly shapedpieces of substantially only indium oxide, the indium, present in saidindium oxide, comprising indium-114m in radioactive equilibrium withindium-114m as main radioactive isotopes, said indium-114m being presentwith a specific activity of at least one MegaBequerel per gram.

[0035] A still further object of the invention is to provide anencapsulated radioactive brachytherapy source comprising a radioactivebrachytherapy source material, said encapsulated radioactivebrachytherapy source comprising a radioactive branchytherapy sourcematerial, said radioactive brachytherapy source material comprisingindium-114m in radioactive equilibrium with indium-114 as mainradioactive isotopes and being made by providing predefinedly shapedpieces of a substantially inorganic and inactive material comprisingindium oxide, the indium in said indium oxide having an abuncance ofindium-113 substantially equal to or greater than its natural abundanceand subjecting the predefinedly shaped pieces of material to neutronirradiation until a predetermined specific activity of indium-114m of atleast one MegaBequerel per gram indium has been reached.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Indium is an element consisting in its natural form of twoisotopes, the stable isotope indium-113 and the ever so slightlyradioactive isotope indium-115. The half life of indium-115 is 4.4*1014years, which for all practical purposes means that it is a stableisotope. The abundance of indium-113 in indium's natural form, i.e. itsnatural abundance, is 4.3%, the remainder being indium-115. Fromhandbooks such as the International Commission on RadiologicalProtection (ICRP); Radionuclide transformations, energy and intensity ofemissions; ICRP Publication 38; Pergamon Press, Oxford, 1983, andFirestone, R. B.; Table of isotopes; eight edition; 1998 update withCD-ROM; John Wiley & Sons; 1998, and from the abovementioned U.S. Pat.No. 5,342,283 it may be seen that one of indium's isotopes, namelyindium-114, emits a beta particle of desired energy for use inendovascular brachytherapy, namely with an average beta energy of 0.78MeV and a maximum beta energy of 2.0 MeV. However, its half life of 72seconds is much too short for practical purposes. As is known from thehandbooks indium-114m is produced by neutron irradiation of indium-113.Indium-114m appears to decay mainly into indium-114 via an isomerictransition with a half life of 49.5 days. Referring to internationalpatent application WO 97/25102, the contents of which are hereinincorporated by reference, by irradiating indium-113 with neutrons aradioactive brachytherapy source material may be obtained that on theone hand has a half life of 49.5 days, the half life of indium-114m, andon the other hand decays with clinically relevant beta radiation, thebeta radiation emitted by indium-114.

[0037] Indium, however, is an extremely soft metal with a very lowmelting point of 156□C. That makes indium as such, i.e. in its metallicform, unfit to be used as a radioactive brachytherapy source material.U.S. Pat. No. 5,342,283 suggests in such a case to encapsulate themetal. In the case of indium that solution is not preferable. Betaradiation, even of the highest energies that are available, has arelatively short range. Such encapsulation leads to extra shielding ofthe beta radiation. Both intensity and energy decrease due to suchencapsulation. Furthermore extra encapsulation also leads to a decreaseof effective volume in which radioactive isotopes may reside. Thus itwill also be more difficult to produce sufficient radioactive isotopesto arrive at a desired activity. Consequently it must be avoided thatencapsulation takes place with more encapsulation material thanabsolutely necessary.

[0038] According to the invention it has been discovered that usingindium oxide provides a material with a high indium content, is muchstronger and harder than elemental indium and has a high melting pointof 1910 □C. The nuclear properties of oxygen are such that irradiationof the material with neutrons to produce In-114m does not result in theproduction of unwanted contaminant isotopes. The atomic concentration ofindium in indium oxide equals ca. 3.1□1022 cm-3 which is not much lowerthan that of elemental indium, namely 3.8□1022 cm-3. Thus the volume ofindium oxide source material needed to achieve a given source activityat a given number of In-114m per mol indium is only slightly larger thanthe volume of metallic indium at that same number of In-114m per molindium, allowing the construction of small, thin sources. Indium oxidehas a density of about 7.2 grams per cubic centimeter, which iscomparable to that of elemental indium, namely 7.3 grams per cubiccentimeter. Thus the amount of self-absorption of beta radiation withina piece of radioactive brachytherapy source material of givendimoensions will not increase due to the use of In2O3 instead of indium.Furthermore oxygen has a low atomic number of 8, so it does not giverise to unwanted increase of the production of unwanted Bremsstrahlungor characteristic X-rays upon self-absorption of the beta radiationwithin the source material.

[0039] The indium oxide may be predefinedly shaped in various shapes andsubsequently subjected to neutron irradiation. This approach minimizesthe handling of radioactive materials resulting in a more economical andreliable production process. A number of techniques is available thatmay be used to shape the indium oxide into the desired shape. Theseinclude for example a number of ceramic forming techniques as describedby for example Reed, James S.; Introduction to the Principles of CeramicProcessing; John Wiley & Sons; New York; 1988 and Terpstra, R. A.; Pex,P. P. A. C.; Vries, A. H. de; Ceramic Processing; Chapman & Hall;London; 1995, that may be used to produce so-called green bodiesapproximating the desired shape but not yet being fully consolidated anddensified and are produced from powders. The green bodies aresubsequently heat treated resulting in the consolidated and densifiedend product.

[0040] One such forming technique to produce green bodies described byReed and by Terpstra et al is so-called dry pressing, which involveseither uniaxial or isostatic pressing of the powder in a mold. In thisway shapes like pellets, blocks, bars, rods, tubes, spheres, ellipsoidor lens-like shapes etc. may be fabricated.

[0041] Alternatively, the powder may be mixed with a suitable binder andpossible other additions, in order to improve the compacting behavior ofthe powder in the mold.

[0042] Alternatively, a sufficiently cohesive and plastic mixture ofpowder, binder and possible other additives may be forced through arigid die, resulting in elongated shapes of uniform cross-section, suchas wires, bars, rods and tubes. This forming technique is calledextrusion.

[0043] Alternatively, a mixture of the powder with a thermoplasticpolymer resin or wax may be heated and injected into a cooled mold. Thisso-called injection molding technique allows the fabrication of simplebut also relatively complex shapes. Current technology allows theinjection molding of bodies with a volume less than about 1 mm3, see forexample Burg, T. v.d.; Metaal en Kunststof; vol. 23/24, pag. 26-27; 1998(in Dutch).

[0044] The green bodies manufactured via techniques such as the onesdescribed above are dried and possibly subjected to surface finishing ifconsidered necessary, and are finally heat treated.

[0045] This heat treatment may include preheating to remove binders andother additives amongst which organic materials like the abovementionedthermoplastic polymer resin or wax and to eliminate gaseous products ofdecomposition and oxidation. This step must be carried out carefully toavoid damaging of the body due to stresses resulting from shrinkage,build up of gas pressure etc.

[0046] Following preheating the bodies are sintered at a temperatureexceeding one half or two thirds of the melting point. The objective ofsintering is to consolidate the product, by joining together theindividual particles resulting in an end product, which has sufficientdensity and strength for the intended application.

[0047] Sintering may be done either under atmospheric pressure or underhigher pressure. Higher pressures generally increase the sintering rate.Sintering may take place under regular atmospheric composition or underselected gas atmospheres. Indium oxide in the form of In2O3 maydissociatively decompose into In2O plus O2, both gases at the sinteringtemperature. This decomposition reaction is occurring in theintermediate and final stages of sintering and leads to gas formationinside the spheres. This makes attainment of a low porosity productdifficult if the reaction rate is too high. Similar problems areexperienced during sintering of SnO2 doped In2O3, generally referred toas ITO. If low porosity In2O3 is to be produced the decompositionreaction must be suppressed. This suppressing can be attained by using asufficiently oxidizing atmosphere and keeping the sintering temperaturelow. Sintering with an elevated oxygen pressure will also be helpful.Improved sintering of indium oxide can be obtained if sintering aidssuch as titanium oxide (0.25-0.5 wt. %) or vanadium oxide (+1 wt. %) areused. These additives are mixed with the indium oxide starting materialand reduce both sintering temperature and limit exaggerated graingrowth, resulting in an end product of near theoretical density and highstrength.

[0048] Information about the sintering of indium oxide and ITO and aboutuseful sintering additives can be found in the following articles, whichalso provide examples of a number of differently shaped indium oxidebodies produced by means of dry uniaxial and isostatic pressing and wetuniaxial pressing: Wit, J. H. W. de; Laheij, M.; Elbers, P. F.; Graingrowth and sintering of In2O3; Science of Ceramics, vol. 9, pag.143-150; Nadaud, N.; Kim, D.-Y.; Boch, P.; Titania as a sinteringadditive in indium oxide ceramics; J. Am. Ceram. Soc., vol. 80, no. 5,pag. 1208-1212; Nadaud, N.; Boch, P.; Influence of TiO2 additives on themicrostructure of In2O3 ceramics; Ceramics International, vol. 22, pag.207-209; Nadaud, N.; Boch, P.; Indium oxide ceramics with titaniaadditions, Key Engineering Materials; vols. 132-136; pag. 928-931;Nadaud, N.; Nanot, M.; Boch, P.; Sintering and electrical properties oftitania and zirconia containing In2O3-SnO2 (ITO) ceramics; J. Am. Ceram.Soc., vol. 77, no. 3, pag.843-846; Son, J-W; Kim, D-Y; Enhanceddensification of In2O3 ceramics by presintering with low pressure (5MPa); J. Am. Ceram. Soc., vol. 81, no. 9, pag. 2489-2492; Bates, J. L.;Griffin, C. W.; Marchant, D. D.; Garnier, J. E.; Electricalconductivity, Seebeck coefficient and structure of In2O3-SnO2; Am.Ceram. Soc. Bull., vol. 65, no. 4, pag. 673-678; Chandra Babu, K. S.;Singh, D.; Srivastava, O. N.; Investigations on the mixed oxide materialTiO2-In2O3 in regard to photoelectrolytic hydrogen production; Semicond.Sci. Technol., vol. 5, pag. 364-368; Vojnovich, T.; Bratton, L. J.;Impurity effects on sintering and electrical resistivity of indiumoxide; Ceram. Bull., vol. 54, no. 2, pag. 216-217; Suzuki, M.; Muraoka,M.; Sawada, Y.; Matsushita, J.; Sintering of indium tin oxide withvanadium oxide additive; Materials Science and Engineering, vol. B54,pag. 46-50.

[0049] As starting material for the above ceramic forming processes,commercially available indium oxide powder may be used. The powder maycontain the natural element indium, with a In-113 abundance of 4.3%, orit may be isotopically enriched to contain an increased percentage ofIn-113. Commercially available enriched material is available with anIn-113 abundance up to almost 100%. The advantage of using enrichedmaterial is a higher specific activity of In-114m upon neutronactivation, thus saving activation costs and allowing the constructionof smaller, thinner encapsulated radioactive brachytherapy sources.

[0050] There may be reasons for beneficiation of the starting powderproperties, as discussed by Reed, for example via comminution by meansof milling to decrease the size of the powder particles in order toimprove the properties of the end product.

[0051] A way to produce fine indium oxide powder via a sol-gel approachis described by Bones, R. J. and Woodhead, J. L., in British Patent1351113. This process allows the production of substantially sphericalor irregularly shaped particles with a mean size between 1 and 200 □m.Shape and size can be controlled by means of a number of processparameters, although the size distribution around the mean is relativelybroad. Specifically mentioned is the possibility to produce particleswithin a size range of 1 and 5 □m for sintering purposes. An alternativesol-gel method is described in Pérez-Maqueda, L. A.; Wang, L.;Metijevic; Nanosize indium hydroxide by peptization of colloidalprecipitates; Langmuir, vol.14, no. 16, pag. 4397-4401. Sinteringadditives as described hereinbefore can be added homogeneously withrelative ease by addition as a nitrite or chloride salt during solpreparation.

[0052] Instead of using the sol-gel approach to produce a powder forsubsequent forming and sintering, one may apply sol-gel chemistry toobtain the desired shape more directly. Examples are sol-gel coatings ofmetal oxides such as indium oxide or ITO onto substrates, the sol-gelproduction of fibers, monoliths, membranes, catalysts etc. as describedin for example Pierre, A. C.; Introduction to sol-gel processing; KluwerAcademic Publishers, 1998 and Jones, R. W.; Fundamental principles ofsol-gel technology, The Institute of Metals, London, 1989.

[0053] A particularly interesting source material comprises indium oxidemicrospheres. An encapsulated radioactive brachytherapy source may beconstructed using one or more of such spheres. The use of multiple,substantially uniformly sized spheres, aligned in a row within a thintubular capsule as described hereinbefore, allows the construction of aso called line source that is particularly suited to irradiate a segmentof a coronary artery. Moreover, in order to facilitate advancement ofsuch a line source via a catheter towards a lesion, the tubular capsulemay be made from a flexible material such as a metal. In this case theuse of indium oxide spheres, as opposed to e.g. a rod, assures that theflexibility of the source is not compromised by the presence of thesource material. Furthermore the use of microspheres consistingprimarily of indium oxide, in which the indium may be enriched inIn-113, minimizes the volume necessary to achieve sufficient activity,thus allowing the construction of a thin source.

[0054] A multitude of references is available which describe how toproduce metal oxide spheres, a category comprising indium oxide spheres.An overview is given in Wilcox, D. L. (1995); Berg, M.: Microspherefabrication and applications: An overview; Mater. Res. Soc. Symp. Proc.,vol. 372, pag. 3-13. Wilcox distinguishes four different methods, towhich the methods described by Pickles (Pickles, C. A, (1983); Mclean,A.; Production of fused refractory Oxide Spheres and Ultrafine OxideParticles in an Extended Arc; Ceramic Bulletin, vol. 62, no. 9, pag.1004-1009), using a plasma arc, and by Dreizin (Dreizin, E. L., (1995);Uniform Solid and Hollow Metal Spheres: Formation in a pulsed Micro-Arcand Applications; Mater. Res. Soc. Symp. Proc., vol. 372, pag. 263-268),employing a micro plasma arc to produce spheres from a consumable anode,must be added.

[0055] Preferably for indium oxide spheres for use in an encapsulatedradioactive brachytherapy source, solid spheres with a diameter of100-1000 micrometer are desired, preferably with a high dimensionalaccuracy. Furthermore it is preferable that the loss of startingmaterial during sphere production is low, especially if relativelycostly enriched starting material is employed. Of the methods describedby Wilcox, by Pickles and by Dreizin the most preferable one appears tobe the method where spheres are made by feeding a liquid through avibrating nozzle, resulting in the formation of droplets with a narrowsize distribution. This process has several variables that can be usedas steering parameters to optimize the production process. Thereforeonly a general outline is presented here.

[0056] In order to obtain spherical pieces of indium oxide by means ofthe vibrating nozzle process a number of steps has to be gone through.It starts with the production of a suitable precursor liquid.

[0057] A liquid precursor for indium oxide can for example be asuspension of indium oxide powder in a suitable solvent. Use of asuspension is described in U.S. Pat. No. 4,671,909 of Torobin. Thesuspension may for example consist of powder particles in watercontaining ammonium alginate, as described in U.S. Pat. No. 5,472,648 ofAlisch et al. Alternatively, the liquid precursor may consist of anindium hydroxide sol, to which for example polyvinyl alcohol is added toadjust the viscosity of the liquid. Methods for the production of indiumhydroxide sols have been mentioned hereinbefore.

[0058] The next step is feeding the liquid through a vibrating nozzle.As a result thereof sphere formation of liquid spheres takes placethrough interfacial forces.

[0059] The process of forming droplets with a narrow size distributionfrom the liquid is extensively described in various articles and patentsincluding Schneider, J. M.; Hendricks, C. D.; Source of uniform sizedliquid droplets; The Review of Scientific Instruments, vol. 35, no. 10,pag. 1349-1350; Lindblad, N. R.; Schneider, J. M.; Production of uniformsized liquid droplets, J. Sci. Instrum., vol. 42, pag. 635-638;Hendricks, C. D.; Babil, S.; Generation of uniform 0.5-10 □m, solidparticles; J. Phys. E: Sc. Instrum., vol. 5, pag. 905-910; Calliger, R.J.; Turnbull, R. J.; Hendricks, C. D.; Hollow drop production byinjection of gas bubbles into a liquid jet; Rev. Sc. Instrum. vol. 48,pag. 846-51; Foster, C. A.; Kim, K.; Turnbull, R. J.; Hendricks, C. D.;Apparatus for producing uniform solid spheres of hydrogen; Rev. Sc.Instrum., vol. 48, pag. 625-631; Hendricks, C. D.; Rosencwaig, A.;Woerner, R. L.; Koo, L. C.; Dressler, J. L.; Sheroman, J. W.; Weinland,S. L.; Jeffries, M.; Fabrication of glass sphere laser fusion targets;J. Nucl. Mat., vol. 85/86, pag. 107-111; Torobin, L. B.; Methods ofmaking hollow porous microspheres; U.S. Pat. No. 4,671,909; Brandau, E.;Huschka, H.; Kadner, M.; Schröder, W.; Method for manufacturingspherical particles out of liquid phase; U.S. Pat. No. 5,183,493; ;Brandau, E.; Huschka, H.; Kadner, M.; Schröder, W.; Process andapparatus for preparing particles from a liquid phase; European patentno.0467221; Theisen, W.; Brauneis, E.; Pirstadt, B.; Process and devicefor producing microspheres; U.S. Pat. No. 5,500,162; Kim, K.;Fabrication of glass micro- and nanospheres from liquid precursors,using droplet generation and sol-gel processing; Mater. Res. Soc. Symp.Proc. vol. 372, pag. 25-32.

[0060] After sphere formation the liquid spheres must be solidified topreserve their form. Solidification of a sol is done via gelation. Theeasiest method to cause gelation in a water based metal hydroxide sol isby increasing the pH value. Two processes are used in the art, calledexternal gelation and internal gelation. External gelation comprisesimmersion of the sol droplets into a fluid that causes fast gelation ofthe sol. Examples of such fluids are ammonia gas and an aqueous solutionof ammonia. In this method gelation is induced by the surroundingmedium. Internal gelation is caused by the addition of a gelling agentto the sol, prior to droplet formation. In this case gelation is notstarting directly, but there is a delay in time before the reactiontakes off.

[0061] Solidification of alginate droplets can be achieved by immersionin an solution containing metal ions, such as an aqueous solution ofCaCl2, resulting in gelation of the alginate solution.

[0062] After gelation the spheres must be washed and then dried toremove the solute. Drying must be executed with some care. Too fastdrying will cause formation of a semi-dry shell and subsequently thesphere will either blow up like a balloon or be fragmented. So a porousaerogel is formed of nanosized indium hydroxide particles. During thedrying stage the sphere is expected to show shrinkage. The amount ofshrinkage is amongst others dependent on the solids content of theindium hydroxide sol.

[0063] Drying is followed by calcination. Calcination is the processwhere the indium hydroxide is transformed into indium oxide particles,by heating them above the decomposition temperature (between 150□C. and280□C.) of the hydroxide. Calcination must be executed with greatcaution. If it proceeds too fast internal steam pressure may build upleading to rupture or explosion of the spheres.

[0064] The resulting porous indium oxide spheres may be sintered toincrease their density and strength. Sintering of indium oxide has beendiscussed hereinbefore. Sintering additives can be added homogeneouslyto the starting liquid by addition as a nitrite or chloride salt duringsol preparation.

[0065] Though indium oxide may be available in pure form just like anyother compound the higher the purity the higher the price. Moreover, itis advantageous to deliberately add certain sintering aids to thestarting material in order to obtain a better end product, as has beenargued hereinbefore. Besides indium oxide certain additional elementsmay be allowed in the indium oxide used in the composition of theradioactive brachytherapy source material.

[0066] A first requirement for such allowed additional elements is thatafter neutron irradiation the radiation of the radioisotopes producedfrom the additional elements (contaminant radioisotopes) does notsignificantly influence the therapeutic dose rate distribution. Thatmeans that if the spatial dose rate distribution of In-114m/In-114 for acertain purpose has been determined based upon a predefined shape ofpure indium oxide (the therapeutic dose rate distribution) additionalradiation originating from the contaminant radioisotopes does notcontribute more to the total dose rate distribution than ten percent ofthe therapeutic dose rate distribution at any point within thetherapeutically relevant region and that the dose rate to personnel dueto additional radiation originating from the contaminant radioisotopesdoes not exceed one hundred percent of the dose rate due to radiationemitted by indium-114m and indium-114.

[0067] A second requirement is that the radiation of contaminantradioisotopes does not significantly raise the dose per treatment of the(hospital) personnel that resides at close distances from the patient.Here significantly means that the dose received by the personnel due tothe contaminant radioisotopes is less than one percent of the dosereceived from the source containing only the In-114m/In-114 isotope.

[0068] A third requirement is that shielding requirements in apparatusesand devices in which sources according to the invention are beingshipped, stored or used do not change.

[0069] These three requirement are met if either of two otherrequirement are met.

[0070] The first other requirement is that the additional elements arerestricted to elements that have such a low neutron activation crosssection in comparison to the cross section for the production of In-114mfrom In-113 that the amount of contaminant radioisotopes remainssufficiently low.

[0071] The second other requirement is that the half life of each of thecontaminant radioisotopes produced from an additional element duringneutron activation is much lower than the 49.5 day half life of In-114m,more specifically that the half life is less than about one day, so thatso-called cooling of the radioactive brachytherapy source material for alimited number of days is sufficient for the contaminant radioisotopesto decay to insignificant levels.

[0072] When either of these two other requirements is met automaticallythe first three requirements are met.

[0073] However, there is a fourth requirement that also has to be met.

[0074] The fourth requirement is that the neutron capture cross sectionof an additional element is less than 200 barn. In that way it isachieved that the indium in the indium oxide is not shielded from theincoming neutrons by the atoms of the additional element.

[0075] It is noted that a very long half life results in a relativelylow activity upon activation, compared to the activity of a radioisotopewith a similar activation cross section but a short half life. Thus anadditional element that meets the above four requirements may still giverise to one or more contaminant radioisotopes with a very long halflife. Therefore a desirable property of the contaminant radioisotopes isthat they have a half life that is not extremely long since this maygive rise to a radioactive waste problem for the radioactivebrachytherapy source material and the encapsulated radioactivebrachytherapy source according to the invention. The group of additionalelements that fit the abovementioned requirements is defined as thegroup consisting of elements that essentially do not become radioactiveduring neutron irradiation and elements that have a half life that issufficiently short so that said selected elements do not emit asignificant amount of beta- or gamma radiation at the time ofapplication of the source material in a radioactive brachytherapy source

[0076] The abovementioned requirements lead to the following allowedadditional elements: hydrogen, lithium, beryllium, carbon, nitrogen,oxygen, fluorine, sodium, magnesium, aluminum, silicon, phosphorus,sulfur, potassium, calcium, titanium, vanadium, manganese, iron, nickel,copper, gallium, germanium, arsenic, strontium, zirconium, niobium,rhodium, tin, iodine, barium, platinum and lead. Preferably theadditional elements are limited to hydrogen, beryllium, carbon, oxygen,fluorine, magnesium, aluminum, silicon, titanium, vanadium andmanganese, since these combine a preferred low atomic number (Z<25) witha very low amount of contaminant radio isotopes at the time of theapplication.

[0077] An increase in specific activity of the radioactive brachytherapysource material, and as a consequence smaller encapsulated radioactivebrachytherapy sources, can be achieved when instead of naturallyavailable indium use is being made of indium enriched in In-113. Indiumenriched with In-113 isotope is commercially available up to enrichmentof close to 100% In-113.

[0078] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention, and all suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

1. A method of manufacturing radioactive brachytherapy source materialcomprising indium-114m as a radioactive isotope, said method comprisingmanufacturing predefinedly shaped pieces of a substantially inorganicand inactive material comprising indium oxide, the indium in said indiumoxide having an abundance of indium-113 substantially equal to orgreater than its natural abundance, any additional elements, present inthe predefinedly shaped pieces, being selected from the group consistingof elements having a sufficiently low neutron cross-section and/or asufficiently short half life such that they emit insignificant amountsof beta- or gamma radiation at the time of application of the sourcematerial in a radioactive brachytherapy source and subsequentlysubjecting the predefinedly shaped pieces of material to neutronirradiation until a specific activity of indium-114m of at least oneMegaBequerel per gram indium has been reached.
 2. The method accordingto claim 1 in which the predefinedly shaped pieces comprisesubstantially only indium oxide.
 3. The method according to claim 1 or 2in which the predefinedly shaped pieces of material are substantiallyspherical.
 4. The method according to claim 3 in which the substantiallyspherical pieces of material have an outer diameter of less than 1 mm.5. The method according to claim 1 further comprising the step ofencapsulating the radioactive brachytherapy source material to providean encapsulated radioactive brachtherapy source comprising substantiallyonly the radioactive brachytherapy source material.